Journal articles: 'LRIG2 protein'

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Razumova, Zoia, Husam Oda, Igor Govorov, Eva Lundin, Ellinor Östensson, David Lindquist, and Miriam Mints. "The Prognostic Role of LRIG Proteins in Endometrial Cancer." Cancers 13, no. 6 (March 17, 2021): 1361. http://dx.doi.org/10.3390/cancers13061361.

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Endometrial cancer (EC) is the most common gynecologic malignancy in Sweden and it has various prognostic factors. The LRIG family is a group of three integral surface proteins with a similar domain organization. The study aimed to explore LRIG family as prognostic factor proteins in EC. The initial study cohort included 100 women with EC who were treated at the Department of Women’s and Children’s Health, Karolinska University Hospital Solna, between 2007 and 2012. We assessed the associations between LRIG protein expression and type, grade, and stage of EC, as well as progression-free and overall survival. Immunohistochemistry results revealed that most women in the analytical sample had >50% LRIG1-, LRIG2- and LRIG3-positive cells. A statistically significant association was observed between having a high number of LRIG3-positive cells and superior overall survival (incidence rate ratio = 0.977; 95% confidence interval: 0.958–0.996, p = 0.019). Moreover, positive LRIG3 staining of the cell membrane was associated with reducing in the risk of death (hazard ratio = 0.23; 95% confidence interval: 0.09–0.57). Our results show that LRIG3 expression might be a prognostic factor in EC. The role of LRIG1 and LRIG2 expression remains to be further investigated.

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Simion, Catalina, Maria Elvira Cedano-Prieto, and Colleen Sweeney. "The LRIG family: enigmatic regulators of growth factor receptor signaling." Endocrine-Related Cancer 21, no. 6 (September 2, 2014): R431—R443. http://dx.doi.org/10.1530/erc-14-0179.

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The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2 and LRIG3) and one member each in flies (Lambik) and worms (Sma-10). LRIGs have stepped into the spotlight as essential regulators of growth factor receptors, including receptor tyrosine and serine/threonine kinases. LRIGs have been found to both negatively (LRIG1 and LRIG3) and positively (Sma-10 and LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood. The most is known about LRIG1, which was recently demonstrated to be a tumor suppressor. Indeed,in vivoexperiments reinforce the essential link between LRIG1 and repression of its targets for tissue homeostasis. LRIG1 has also been identified as a stem cell marker and regulator of stem cell quiescence in a variety of tissues, discussed within. Comparably, less is known about LRIG2 and LRIG3, although studies to date suggest that their functions are largely distinct from that of LRIG1 and that they likely do not serve as growth/tumor suppressors. Finally, the translational applications of expressing soluble forms of LRIG1 in LRIG1-deficient tumors are being explored and hold tremendous promise.

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Hoesl, Christine, Thomas Fröhlich, Jennifer E. Hundt, Hermann Kneitz, Matthias Goebeler, Ronald Wolf, Marlon R. Schneider, and Maik Dahlhoff. "The transmembrane protein LRIG2 increases tumor progression in skin carcinogenesis." Molecular Oncology 13, no. 11 (October 21, 2019): 2476–92. http://dx.doi.org/10.1002/1878-0261.12579.

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Páez, David, Melissa Janae Labonte, Laia Paré, Dongyun Yang, Pierre Oliver Bohanes, Armin Gerger, Wu Zhang, et al. "Use of leucine-rich and immunoglobulin-like domains germ-line polymorphisms to predict clinical outcome in metastatic colorectal cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e14052-e14052. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14052.

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e14052 Background: Leucine-rich and immunoglobulin-like domains (LRIG) 1, 2, and 3 are integral membrane proteins recently discovered as regulators of the epidermal growth factor signalling. LRIG1 negatively regulates growth factor signaling and increasing evidence indicates that LRIG1 is a tumor suppressor in certain cancer types. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some colorectal tumors.We postulate that polymorphisms located in the LRIG1 gene could influence the EGFR signalling pathway and be related with the clinical outcome in metastatic colorectal cancer (mCRC). Methods: This study included 318 patients with mCRC treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Common and putatively functional polymorphisms in the LRIG genes were selected using public literature resources and databases (NCBI, PubMed, db SNP, Ensembl and GeneCards). Whole blood samples were analyzed for germline polymorphisms by direct DNA-sequencing. Overall survival (OS) was evaluated according to each genotype. Furthermore, polymorphisms with suggestive statistical significance were replicated in an independent validation cohort of 126 Spanish mCRC. Results: In a preliminary analysis, two non-synonymous (c3158A>C and c1843A>G) and two synonymous (c2221T>C and c1317C>T) polymorphisms in the LRIG1 gene were selected. There were significant interactions between LRIG1 c1317C>T polymorphisms and clinical outcome. OS was lower for patients harboring T/T genotype (median=11.9 months, 95% C.I (3.5-16 months) than for patients with the C/C or C/T genotypes (median=14.5 months; 95% C.I (12.2-18.3 months); p= 0.04, log-rank test) and the association was also significant in the validation cohort (p=0.01). Conclusions: In this study, we identified common germline variants in LRIG1 gene predicting clinical outcome in patients with mCRC. Although, no functionality has been documented for these SNPs to date, our clinical data suggest that these polymorphisms may affect the mRNA stability and/or translation efficiency of the gene.

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Breton, Amandine, Laura Sonzogni, Andria Theodorou, Suleyman Aktuna, Stephan Menzel, Frank Grosveld, Sjaak Philipsen, and Swee Lay Thein. "ASH1L: A Novel Beta-Globin Gene Regulator in Humans?" Blood 126, no. 23 (December 3, 2015): 641. http://dx.doi.org/10.1182/blood.v126.23.641.641.

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Abstract BACKGROUND: We have previously described a unique English family with beta-thalassemia trait which was not linked to the β-globin gene locus (Thein, Wood, Wickramasinghe, & Galvin, 1993). This suggested involvement of a trans-acting factor required for full activation of the β-globin gene locus. Such a factor is likely to be a modulator of disease severity in sickle cell disease and beta-thalassemia which could provide insights for novel therapeutic targets in the beta-globinopathies. RESULTS: We applied whole genome scan (WGS) to 2 affected and 2 unaffected subjects of the English family. The familial segregation suggested a dominant transmission mode; WGS identified 15 genes as potentially causative to the phenotype, with four genes located on chromosome 1, four on chromosome 3, three on chromosome 20, and one on chromosome 6, chromosome 8, chromosome 10 and chromosome 19. Sanger sequence analysis on 23 family members spanning three generations, including the 4 individuals that were subjected to WGS, revealed that the 15 variants were not artefacts of the WGS and that all variants were present in the 2 affected but not in the 2 unaffected individuals. Furthermore we found that 4 of the 15 variants were consistently and uniquely present in all 9 affected but absent in the unaffected family members. We performed association linkage analysis using the 15 markers in the whole family, and confirmed that the phenotype was closely linked to the 4 genes that were inherited as a block spanning the centromere on chromosome 1. We concluded that the region containing these 4 genes most likely harbours the mutation causing the phenotype. Among the 4 candidate genes, 2 were not expressed in erythroid cells, but the other 2 - one encoding an integral membrane protein (LRIG2) and the other one encoding a methyl transferase (ASH1L)- were expressed in erythroid cells. Functional studies for these two genes were performed on primary human erythroid progenitor cells (hEPCs) in culture. In following the kinetics of the 2 candidates during differentiation of hEPCs, we observed that the expression of ASH1L increased at later stages of differentiation, where LRIG2 displayed a less dramatic change of expression. Moreover, ASH1L has previously been found to occupy transcribed chromatin domains and methylate histone tails in vitro (Gregory et al., 2007; Miyazaki et al., 2013; Tanaka et al., 2011). In undifferentiated mouse embryonic stem cells there is no ASH1L recruitment to the β-globin gene locus but upon erythroid differentiation the protein is recruited to the transcribed portion of the gene (Gregory et al., 2007). This suggests an involvement of ASH1L in beta-globin activation in erythroid lineages. We used shRNA lentiviruses to generate knock-down (KD) of ASH1L and obtained over 65-75% KD of the gene. In hEPCs treated with the shRNA lentivirus, we observed a slight decrease in beta-globin expression compared to the control hEPCs. The α/β-globin and α/(β+γ) globin ratios were also affected by the gene knock-down. ChIP-qPCR was performed to assess the enrichment of the ASH1L protein at β-globin promoter region. The results show that enrichment of ASH1L at the β-globin promoter correlates with the β-globin expression in cells. CONCLUSIONS: These results suggest that ASH1L is responsible for the phenotype observed in the English family and act in differentiating hEPCs as a trans-acting factor for full beta-globin gene activation. Further ChIP analysis to assess the binding of the protein to the beta-globin locus during hEPCs differentiation and under KD condition will provide us with a better understanding of the influence of the methyl transferase on β-globin activation. The replication of the patient mutation in vitro using CRISPR technology will provide the model to study fully the impact of the mutation on the phenotype described in the original paper. These findings could provide new insights for therapeutic targets for beta-globinopathies. Disclosures No relevant conflicts of interest to declare.

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Neirinckx, V., A. Hau, A. Schuster, S. Fritah, A. Chevigné, M. H. H. Schmidt, and S. P. Niclou. "P11.09 Pan-RTK inhibition of sLRIG1 mediates AXL downregulation in Glioblastoma." Neuro-Oncology 21, Supplement_3 (August 2019): iii44. http://dx.doi.org/10.1093/neuonc/noz126.155.

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Abstract INTRODUCTION Aberrant regulation of receptor tyrosine kinase (RTK) activity is characteristic of Glioblastoma (GBM). However, RTK-based targeted therapies have been largely unsuccessful in GBM patients, partially due to the complexity and redundance of RTK signaling. LRIG1 (Leucine-rich Repeats and ImmunoGlobulindomains protein 1) is known as an endogenous inhibitor of epidermal growth factor receptor (EGFR) during health and disease, however its mechanism of action is poorly understood. We previously showed that the soluble form of LRIG1 potently inhibits of GBM growth in vivo, irrespective of EGFR expression level and status, suggesting the involvement of other RTKs. Here, we aimed to shed light on the molecular mechanisms underlying its anti-cancer activity. MATERIAL AND METHODS We generated a recombinant human soluble LRIG1 protein by expressing LRIG1 ectodomain in insect cells via baculovirus infection and subsequent His-tag purification. rh-sLRIG1 was applied in the medium of classical GBM cell lines, patient-derived GBM stem-like cells and patient-derived 3D tumor organoids. Using different cell-based assays, cell proliferation, invasion, cell morphology, as well as protein expression and protein-protein interactions were investigated. RESULTS We find that recombinant sLRIG1 efficiently reduces proliferation, invasion and viability of GBM cells and patient-derived organoids, and modulates cytoskeleton proteins and cell shape. In line with previous data, the effect of recombinant sLRIG1 is independent of EGFR expression. Interestingly sLRIG1 regulates several RTKs by direct protein downregulation, including AXL, while EGFR expression is not affected. At the molecular level, we find that sLRIG1 interferes with AXL dimerization, while no protein interaction with EGFR is detected. CONCLUSION We identify AXL as a novel LRIG1 target and provide evidence that sLRIG1-mediated RTK downregulation requires direct protein-protein interaction. These data pave the way for a potential therapeutic application of recombinant sLRIG1 in the inhibition of growth factor signaling in GBM.

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Neirinckx, Virginie, Ann-Christin Hau, Anne Schuster, Sabrina Fritah, Andy Chevigné, Mirko H. Schmidt, and Simone Niclou. "CSIG-04. PAN-RTK INHIBITION OF sLRIG1 MEDIATES AXL DOWNREGULATION IN GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi44. http://dx.doi.org/10.1093/neuonc/noz175.175.

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Abstract INTRODUCTION Aberrant regulation of receptor tyrosine kinase (RTK) activity is characteristic of Glioblastoma (GBM). However, RTK-based targeted therapies have been largely unsuccessful in GBM patients, partially due to the complexity and redundance of RTK signaling. LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains 1) is an important endogenous inhibitor of epidermal growth factor receptor (EGFR) during health and disease, however its mechanism of action is poorly understood. We previously showed that the soluble form of LRIG1 potently inhibits GBM growth in vivo, irrespective of EGFR expression level and status, suggesting the involvement of other RTKs. Here, we aimed to shed light on the molecular mechanisms underlying its anti-cancer activity. MATERIAL AND METHODS We generated a recombinant human soluble LRIG1 protein (rh-sLRIG1) by expressing LRIG1 ectodomain in insect cells via baculovirus infection and subsequent His-tag purification. rh-sLRIG1 was used to treat patient-derived GBM stem-like cells, classical GBM cell lines and patient-derived 3D tumor organoids. Using different cell-based assays, cell proliferation, invasion, cell morphology, as well as protein expression and protein-protein interactions were investigated. RESULTS We find that recombinant sLRIG1 efficiently reduced proliferation, invasion and viability of GBM cells and patient-derived organoids, and modulated cytoskeleton proteins and cell shape. In line with previous data, the effect of recombinant sLRIG1 was independent of EGFR expression. Interestingly sLRIG1 impacted multiple RTKs including AXL, by direct protein downregulation, while EGFR expression was not affected. At the molecular level, we find that sLRIG1 interfereed with AXL dimerization, while no protein interaction with EGFR was detected. CONCLUSION We identify AXL as a novel LRIG1 target and provide evidence that sLRIG1-mediated RTK downregulation requires direct protein-protein interaction. These data pave the way for a potential therapeutic application of recombinant sLRIG1 in the inhibition of growth factor signaling in GBM.

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Choi, Eunyoung, Tyler L. Lantz, Gregory Vlacich, Theresa M. Keeley, Linda C. Samuelson, Robert J. Coffey, James R. Goldenring, and Anne E. Powell. "Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach." Gut 67, no. 9 (August 16, 2017): 1595–605. http://dx.doi.org/10.1136/gutjnl-2017-313874.

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ObjectiveLrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice.DesignWe performed lineage labelling using Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) or R26R-LacZ/+ (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP-marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1-CreERT2/CreERT2 (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury.ResultsLrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy.ConclusionsLrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach.

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Wang, Yuchun, Liqi Fu, Bo Liu, Xiaomin Wang, Kai Wang, and Ming Ye. "Construction of human LRIG1-TAT fusions and TAT-mediated LRIG1 protein delivery." Biomedicine & Pharmacotherapy 69 (February 2015): 396–401. http://dx.doi.org/10.1016/j.biopha.2014.12.034.

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Shattuck, David L., Jamie K. Miller, Melanie Laederich, Melanie Funes, Heidi Petersen, Kermit L. Carraway, and Colleen Sweeney. "LRIG1 Is a Novel Negative Regulator of the Met Receptor and Opposes Met and Her2 Synergy." Molecular and Cellular Biology 27, no. 5 (December 18, 2006): 1934–46. http://dx.doi.org/10.1128/mcb.00757-06.

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ABSTRACT The Met receptor tyrosine kinase regulates a complex array of cellular behaviors collectively known as “invasive growth.” While essential for normal development and wound repair, this program is frequently co-opted by tumors to promote their own growth, motility, and invasion. Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with poor patient prognosis. Previous studies indicate that Met receptor levels are governed in part by cbl-mediated ubiquitination and degradation, and uncoupling of Met from cbl-mediated ubiquitination promotes its transforming activity. Here we describe a novel mechanism for Met degradation. We find that the Met receptor interacts with the transmembrane protein LRIG1 independent of hepatocyte growth factor (HGF) stimulation and that LRIG1 destabilizes the Met receptor in a cbl-independent manner. Overexpression of LRIG1 destabilizes endogenous Met receptor in breast cancer cells and impairs their ability to respond to HGF. LRIG1 knockdown increases Met receptor half-life, indicating that it plays an essential role in Met degradation. Finally, LRIG1 opposes Met synergy with the ErbB2/Her2 receptor tyrosine kinase in driving cellular invasion. We conclude that LRIG1 is a novel suppressor of Met function, serving to regulate cellular receptor levels by promoting Met degradation in a ligand- and cbl-independent manner.

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Nilsson, Jonas, Anna Starefeldt, Roger Henriksson, and Håkan Hedman. "LRIG1 protein in human cells and tissues." Cell and Tissue Research 312, no. 1 (March 18, 2003): 65–71. http://dx.doi.org/10.1007/s00441-003-0697-1.

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Powell, Anne E., Gregory Vlacich, Zhen-Yang Zhao, Eliot T. McKinley, M. Kay Washington, H. Charles Manning, and Robert J. Coffey. "Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 1 (July 1, 2014): G16—G23. http://dx.doi.org/10.1152/ajpgi.00358.2013.

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Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli ( APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1+) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1+ cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.

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Karlsson, Terese, Elisabeth B. Mark, Roger Henriksson, and Håkan Hedman. "Redistribution of LRIG Proteins in Psoriasis." Journal of Investigative Dermatology 128, no. 5 (May 2008): 1192–95. http://dx.doi.org/10.1038/sj.jid.5701175.

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Hsu, Han-Lin, Hong-Kai Chen, Chi-Hao Tsai, Po-Lin Liao, Yen-Ju Chan, Yu-Cheng Lee, Chen-Chen Lee, and Ching-Hao Li. "Aryl Hydrocarbon Receptor Defect Attenuates Mitogen-Activated Signaling through Leucine-Rich Repeats and Immunoglobulin-like Domains 1 (LRIG1)-Dependent EGFR Degradation." International Journal of Molecular Sciences 22, no. 18 (September 15, 2021): 9988. http://dx.doi.org/10.3390/ijms22189988.

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Aryl hydrocarbon receptor (AHR) genomic pathway has been well-characterized in a number of respiratory diseases. In addition, the cytoplasmic AHR protein may act as an adaptor of E3 ubiquitin ligase. In this study, the physiological functions of AHR that regulate cell proliferation were explored using the CRISPR/Cas9 system. The doubling-time of the AHR-KO clones of A549 and BEAS-2B was observed to be prolonged. The attenuation of proliferation potential was strongly associated with either the induction of p27Kip1 or the impairment in mitogenic signal transduction driven by the epidermal growth factor (EGF) and EGF receptor (EGFR). We found that the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a repressor of EGFR, was induced in the absence of AHR in vitro and in vivo. The LRIG1 tends to degrade via a proteasome dependent manner by interacting with AHR in wild-type cells. Either LRIG1 or a disintegrin and metalloprotease 17 (ADAM17) were accumulated in AHR-defective cells, consequently accelerating the degradation of EGFR, and attenuating the response to mitogenic stimulation. We also affirmed low AHR but high LRIG1 levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients. This might partially elucidate the sluggish tissue repairment and developing inflammation in COPD patients.

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Rafidi, Hanine, Francisco Mercado, Michael Astudillo, William H. D. Fry, Matthew Saldana, Kermit L. Carraway, and Colleen Sweeney. "Leucine-rich Repeat and Immunoglobulin Domain-containing Protein-1 (Lrig1) Negative Regulatory Action toward ErbB Receptor Tyrosine Kinases Is Opposed by Leucine-rich Repeat and Immunoglobulin Domain-containing Protein 3 (Lrig3)." Journal of Biological Chemistry 288, no. 30 (May 30, 2013): 21593–605. http://dx.doi.org/10.1074/jbc.m113.486050.

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Ghasimi, Soma, Hannu Haapasalo, Mine Eray, Katariina Korhonen, Thomas Brännström, Håkan Hedman, and Ulrika Andersson. "Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression." Journal of Neuro-Oncology 108, no. 3 (April 8, 2012): 435–41. http://dx.doi.org/10.1007/s11060-012-0856-x.

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Kim, Jo, Jang, Nguyen, Yun, Ko, Shin, et al. "PAC-5 Gene Expression Signature for Predicting Prognosis of Patients with Pancreatic Adenocarcinoma." Cancers 11, no. 11 (November 7, 2019): 1749. http://dx.doi.org/10.3390/cancers11111749.

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Pancreatic adenocarcinoma (PAC) is one of the most aggressive malignancies. Intratumoural molecular heterogeneity impedes improvement of the overall survival rate. Current pathological staging system is not sufficient to accurately predict prognostic outcomes. Thus, accurate prognostic model for patient survival and treatment decision is demanded. Using differentially expressed gene analysis between normal pancreas and PAC tissues, the cancer-specific genes were identified. A prognostic gene expression model was computed by LASSO regression analysis. The PAC-5 signature (LAMA3, E2F7, IFI44, SLC12A2, and LRIG1) that had significant prognostic value in the overall dataset was established, independently of the pathological stage. We provided evidence that the PAC-5 signature further refined the selection of the PAC patients who might benefit from postoperative therapies. SLC12A2 and LRIG1 interacted with the proteins that were implicated in resistance of EGFR kinase inhibitor. DNA methylation was significantly involved in the gene regulations of the PAC-5 signature. The PAC-5 signature provides new possibilities for improving the personalised therapeutic strategies. We suggest that the PAC-5 genes might be potential drug targets for PAC.

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Hoesl, Christine, Thomas Fröhlich, Christian Posch, Hermann Kneitz, Matthias Goebeler, Marlon R. Schneider, and Maik Dahlhoff. "The transmembrane protein LRIG1 triggers melanocytic tumor development following chemically induced skin carcinogenesis." Molecular Oncology 15, no. 8 (March 31, 2021): 2140–55. http://dx.doi.org/10.1002/1878-0261.12945.

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Gumienny, Tina L., Lesley MacNeil, Cole M. Zimmerman, Huang Wang, Lena Chin, Jeffrey L. Wrana, and Richard W. Padgett. "Caenorhabditis elegans SMA-10/LRIG Is a Conserved Transmembrane Protein that Enhances Bone Morphogenetic Protein Signaling." PLoS Genetics 6, no. 5 (May 20, 2010): e1000963. http://dx.doi.org/10.1371/journal.pgen.1000963.

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Abraira, Victoria E., Andrew F. Tucker, and Lisa V. Goodrich. "The Ig superfamily protein Lrig3 controls inner ear morphogenesis by regulating Netrin-1 expression." Developmental Biology 319, no. 2 (July 2008): 504. http://dx.doi.org/10.1016/j.ydbio.2008.05.133.

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Hoesl, C., R. Wolf, E. Wolf, M. Schneider, and M. Dahlhoff. "078 The transmembrane protein LRIG1 regulates receptor tyrosine kinases in skin development and homeostasis." Journal of Investigative Dermatology 137, no. 10 (October 2017): S206. http://dx.doi.org/10.1016/j.jid.2017.07.388.

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Mao, Feng, Baofeng Wang, Qungen Xiao, Fangling Cheng, Ting Lei, and Dongsheng Guo. "LRIG proteins in glioma: Functional roles, molecular mechanisms, and potential clinical implications." Journal of the Neurological Sciences 383 (December 2017): 56–60. http://dx.doi.org/10.1016/j.jns.2017.10.025.

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Ranhem, Cecilia, Gabriella Lillsunde Larsson, Håkan Hedman, David Lindquist, Mats G. Karlsson, Ann-Cathrin Hellström, Ellinor Östensson, Bengt Sorbe, Kristina Hellman, and Sonia Andersson. "Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma." PLOS ONE 12, no. 8 (August 25, 2017): e0183816. http://dx.doi.org/10.1371/journal.pone.0183816.

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Bhuju, Jyoti, Kristin M. Olesen, Clarisse S. Muenyi, Tejesh S. Patel, Robert W. Read, Lauren Thompson, Omar Skalli, et al. "Cutaneous Effects of In Utero and Lactational Exposure of C57BL/6J Mice to 2,3,7,8-Tetrachlorodibenzo-p-dioxin." Toxics 9, no. 8 (August 20, 2021): 192. http://dx.doi.org/10.3390/toxics9080192.

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To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 μg TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDD-exposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects.

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Laederich, Melanie B., Melanie Funes-Duran, Lily Yen, Ellen Ingalla, Xiuli Wu, Kermit L. Carraway, and Colleen Sweeney. "The Leucine-rich Repeat Protein LRIG1 Is a Negative Regulator of ErbB Family Receptor Tyrosine Kinases." Journal of Biological Chemistry 279, no. 45 (September 1, 2004): 47050–56. http://dx.doi.org/10.1074/jbc.m409703200.

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Gao, Yang, Chengtao Liu, Xiaoling Zhao, Chaojun Liu, Wenzhi Bi, and Jinpeng Jia. "hsa_circ_0000006 induces tumorigenesis through miR-361- 3p targeting immunoglobulin-like domains protein 1 (LRIG1) in osteosarcoma." Annals of Translational Medicine 9, no. 15 (August 2021): 1242. http://dx.doi.org/10.21037/atm-21-3076.

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Eisenstat, David D., and Spencer B. Gibson. "RIGging functional outcomes in glioma cells: New insights into LRIG proteins in malignant gliomas." Cancer Biology & Therapy 8, no. 11 (June 2009): 1024–26. http://dx.doi.org/10.4161/cbt.8.11.8749.

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Guo, Dongsheng, Jonas Nilsson, Hannu Haapasalo, Olayinka Raheem, Tommy Bergenheim, Håkan Hedman, and Roger Henriksson. "Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors." Acta Neuropathologica 111, no. 3 (March 2006): 238–46. http://dx.doi.org/10.1007/s00401-006-0032-5.

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Faraz, Mahmood, Carl Herdenberg, Camilla Holmlund, Roger Henriksson, and Håkan Hedman. "A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors." Journal of Biological Chemistry 293, no. 9 (January 9, 2018): 3421–35. http://dx.doi.org/10.1074/jbc.m117.807487.

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Wu, Xuping, Håkan Hedman, Michael Bergqvist, Stefan Bergström, Roger Henriksson, Joachim Gullbo, Johan Lennartsson, Patrik Hesselius, and Simon Ekman. "Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity." Acta Oncologica 51, no. 1 (March 18, 2011): 69–76. http://dx.doi.org/10.3109/0284186x.2011.562239.

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Karlsson, Terese, Samuel Kvarnbrink, Camilla Holmlund, Johan Botling, Patrick Micke, Roger Henriksson, Mikael Johansson, and Håkan Hedman. "LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease." Lung Cancer 125 (November 2018): 174–84. http://dx.doi.org/10.1016/j.lungcan.2018.09.017.

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Guo, Dongsheng, Lin Han, Kai Shu, Jian Chen, and Ting Lei. "Down-regulation of leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) in HP75 pituitary adenoma cell line." Journal of Huazhong University of Science and Technology 27, no. 1 (February 2007): 91–94. http://dx.doi.org/10.1007/s11596-007-0126-x.

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Zhang, Qianqian, Wenhua Shi, Qingting Wang, Yanting Zhu, Cui Zhai, Jian Wang, Xin Yan, Limin Chai, and Manxiang Li. "Clinicopathological and prognostic significance of leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) in malignant tumors: A meta-analysis." Journal of Cancer 9, no. 16 (2018): 2895–909. http://dx.doi.org/10.7150/jca.24749.

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Laederich, Melanie B., Melanie Funes-Duran, Lily Yen, Ellen Ingalla, Xiuli Wu, Kermit L. Carraway, and Colleen Sweeney. "The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. Vol. 279 (2004) 47050–47056." Journal of Biological Chemistry 279, no. 50 (December 2004): 52806. http://dx.doi.org/10.1016/s0021-9258(20)67731-6.

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Jang, Bo Gun, Hye Sung Kim, Jeong Mo Bae, Woo Ho Kim, Chang Lim Hyun, and Gyeong Hoon Kang. "Expression Profile and Prognostic Significance of EPHB3 in Colorectal Cancer." Biomolecules 10, no. 4 (April 13, 2020): 602. http://dx.doi.org/10.3390/biom10040602.

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The protein tyrosine kinase Ephrin type-B receptor 3 (EPHB3) is expressed in cells at the base of intestinal crypts, acting as a cellular guide in the maintenance of intestinal crypt architecture. We aimed to investigate the expression profile of EPHB3 in colorectal precancerous lesions and colorectal cancers (CRCs), and assess its prognostic value. EPHB3 expression was higher in CRCs than in normal mucosa and was associated with the intestinal stem cell markers EPHB2, OLFM4, LRIG1, and a proposed cancer stem cell marker, CD44. Enhanced EPHB3 expression significantly declined during the transformation from adenoma to carcinoma and as the tumor invaded into deeper tissue layers. Namely, a substantial reduction of EPHB3 expression was observed in the budding cancer cells at the invasive tumor fronts, which was more extensive than E-cadherin downregulation. In an azoxymethane/dextran sulfate sodium-induced, colitis-associated, CRC model, EPHB3 expression increased along with tumor development. In a large cohort of CRC patients, EPHB3 positivity was observed in 24% of 610 CRCs and was negatively correlated with tumor differentiation, lympho-vascular invasion, and tumor, node, and metastasis stages. EPHB3 was positively associated with microsatellite instability but was associated with neither CpG island methylation, nor with KRAS and BRAF mutations. Notably, EPHB3 positivity was associated with better clinical outcomes, although it was not an independent prognostic marker. Overexpression of EPHB3 in the colon cancer cell line, DLD1, led to decreased cell growth and migration and reduced mitogen-activated protein kinase signaling. Taken together, our data demonstrate the suppressive role of EPHB3 in CRC progression.

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Phillips, Marjorie A., Angela Cánovas, Pei-Wen Wu, Alma Islas-Trejo, Juan F. Medrano, and Robert H. Rice. "Parallel responses of human epidermal keratinocytes to inorganic SbIII and AsIII." Environmental Chemistry 13, no. 6 (2016): 963. http://dx.doi.org/10.1071/en16019.

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Environmental contextIncreasing commercial use of antimony is raising its environmental presence and thus possible effects on humans and ecosystems. An important uncertainty is the risk that exposure poses for biological systems. The present work explores the similarity in response of human epidermal keratinocytes, a known target cell type, to antimony and arsenic, where deleterious consequences of exposure to the latter are better known. AbstractSbIII and AsIII are known to exhibit similar chemical properties, but the degree of similarity in their effects on biological systems merits further exploration. The present work compares the responses of human epidermal keratinocytes, a known target cell type for arsenite-induced carcinogenicity, to these metalloids after treatment for 1 week at environmentally relevant concentrations. Previous work with these cells has shown that arsenite and antimonite have parallel effects in suppressing differentiation, altering levels of several critical enzymes and maintaining colony-forming ability. More globally, protein profiling now reveals parallels in SbIII and AsIII effects. The more sensitive technique of transcriptional profiling also shows considerable parallels. Thus, gene expression changes were almost entirely in the same directions for the two treatments, although the degree of change was sometimes significantly different. Inspection of the changes revealed that RYR1 and LRIG1 were among the genes strongly suppressed, consistent with reduced calcium-dependent differentiation and maintenance of epidermal growth factor-dependent proliferative potential. Moreover, levels of microRNAs in the cells were altered in parallel, with nearly 90% of the 198 most highly expressed ones being suppressed. Among these was miR-203, which is known to decrease proliferative potential. Finally, both SbIII and AsIII were seen to attenuate bone morphogenetic protein 6 induction of dual-specificity phosphatases 2 and 14, consistent with maintaining epidermal growth factor receptor signalling. These findings raise the question of whether SbIII, like AsIII, could act as a human skin carcinogen.

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Phillips, Marjorie A., Angela Cánovas, Pei-Wen Wu, Alma Islas-Trejo, Juan F. Medrano, and Robert H. Rice. "Corrigendum to: Parallel responses of human epidermal keratinocytes to inorganic SbIII and AsIII." Environmental Chemistry 16, no. 1 (2019): 80. http://dx.doi.org/10.1071/en16019_co.

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Environmental contextIncreasing commercial use of antimony is raising its environmental presence and thus possible effects on humans and ecosystems. An important uncertainty is the risk that exposure poses for biological systems. The present work explores the similarity in response of human epidermal keratinocytes, a known target cell type, to antimony and arsenic, where deleterious consequences of exposure to the latter are better known. AbstractSbIII and AsIII are known to exhibit similar chemical properties, but the degree of similarity in their effects on biological systems merits further exploration. The present work compares the responses of human epidermal keratinocytes, a known target cell type for arsenite-induced carcinogenicity, to these metalloids after treatment for 1 week at environmentally relevant concentrations. Previous work with these cells has shown that arsenite and antimonite have parallel effects in suppressing differentiation, altering levels of several critical enzymes and maintaining colony-forming ability. More globally, protein profiling now reveals parallels in SbIII and AsIII effects. The more sensitive technique of transcriptional profiling also shows considerable parallels. Thus, gene expression changes were almost entirely in the same directions for the two treatments, although the degree of change was sometimes significantly different. Inspection of the changes revealed that RYR1 and LRIG1 were among the genes strongly suppressed, consistent with reduced calcium-dependent differentiation and maintenance of epidermal growth factor-dependent proliferative potential. Moreover, levels of microRNAs in the cells were altered in parallel, with nearly 90% of the 198 most highly expressed ones being suppressed. Among these was miR-203, which is known to decrease proliferative potential. Finally, both SbIII and AsIII were seen to attenuate bone morphogenetic protein 6 induction of dual-specificity phosphatases 2 and 14, consistent with maintaining epidermal growth factor receptor signalling. These findings raise the question of whether SbIII, like AsIII, could act as a human skin carcinogen.

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King, Jeffrey B., Richard J. von Furstenberg, Brian J. Smith, Kirk K. McNaughton, Joseph A. Galanko, and Susan J. Henning. "CD24 can be used to isolate Lgr5+ putative colonic epithelial stem cells in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 4 (August 15, 2012): G443—G452. http://dx.doi.org/10.1152/ajpgi.00087.2012.

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A growing body of evidence has implicated CD24, a cell-surface protein, as a marker of colorectal cancer stem cells and target for antitumor therapy, although its presence in normal colonic epithelium has not been fully characterized. Previously, our group showed that CD24-based cell sorting can be used to isolate a fraction of murine small intestinal epithelial cells enriched in actively cycling stem cells. Similarly, we hypothesized that CD24-based isolation of colonic epithelial cells would generate a fraction enriched in actively cycling colonic epithelial stem cells (CESCs). Immunohistochemistry performed on mouse colonic tissue showed CD24 expression in the bottom half of proximal colon crypts and the crypt base in the distal colon. This pattern of distribution was similar to enhanced green fluorescent protein (EGFP) expression in Lgr5-EGFP mice. Areas expressing CD24 contained actively proliferating cells as determined by ethynyl deoxyuridine (EdU) incorporation, with a distinct difference between the proximal colon, where EdU-labeled cells were most frequent in the midcrypt, and the distal colon, where they were primarily at the crypt base. Flow cytometric analyses of single epithelial cells, identified by epithelial cell adhesion molecule (EpCAM) positivity, from mouse colon revealed an actively cycling CD24+ fraction that contained the majority of Lgr5-EGFP+ putative CESCs. Transcript analysis by quantitative RT-PCR confirmed enrichment of active CESC markers [leucine-rich-repeat-containing G protein-coupled receptor 5 (Lgr5), ephrin type B receptor 2 (EphB2), and CD166] in the CD24+EpCAM+ fraction but also showed enrichment of quiescent CESC markers [leucine-rich repeats and immunoglobin domains (Lrig), doublecortin and calmodulin kinase-like 1 (DCAMKL-1), and murine telomerase reverse transcriptase (mTert)]. We conclude that CD24-based sorting in wild-type mice isolates a colonic epithelial fraction highly enriched in actively cycling and quiescent putative CESCs. Furthermore, the presence of CD24 expression in normal colonic epithelium may have important implications for the use of anti-CD24-based colorectal cancer therapies.

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Nikpour, Maryam, Andrea Pellagatti, Martin Jädersten, Ann-Mari Forsblom, James S. Wainscoat, Jacqueline Boultwood, and Eva Hellström-Lindberg. "Gene Expression Profiling of Day 7 Erythroblasts from RARS Before and after Treatment with G-CSF." Blood 110, no. 11 (November 16, 2007): 2427. http://dx.doi.org/10.1182/blood.v110.11.2427.2427.

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Abstract Refractory Anemia with Ringed Sideroblasts (RARS) is characterized by severe ineffective erythropoesis, cytochrome c release, and mitochondrial iron overload. (Tehranchi, 2003). Granulocyte-CSF inhibit erythroid apoptosis in vitro as well as in vivo (Tehranchi 2005) The molecular mechanisms underlying the erythroid apoptosis in RARS and the effects of G-CSF were studied by gene expression profiling of erythroblasts from 8 healthy controls and 6 RARS patients. CD34+ selected marrow cells were cultured for 7 days in Iscove’s medium with 15% BIT9500. At day 7 an aliquot of RARS cells were treated with G-CSF (100ng/ml) for 4 hours. The gene expression profiles were determined using Affymetrix, U133 Plus2.0 chips (Pellagatti, 2006). Statistical analysis showed that 1426 probe-sets were significantly differentially expressed (P<0.01) between untreated and G-CSF treated RARS samples, and healthy controls. Hierarchical clustering separated these groups into distinct clusters. 22 genes were significantly up-regulated by ≥2-fold in all RARS samples and included CCND2, DLK1, PPM1A and TBC1D8. 35 genes were significantly down-regulated by ≥2-fold, including LRIG1, ABCB7 and MLL3. RARS erythroblasts showed dysregulation of several genes involved in proliferation, apoptosis and iron transport. For instance CCND2 and TBC1D8, positive regulators of proliferation, were up-regulated in RARS, whereas LRIG1, a negative regulator of proliferation, was down-regulated. PPM1A, whose function leads to G2/M cell cycle arrest and apoptosis via p53 activation, was also up-regulated. ABCB7, involved in the transfer of iron from mitochondria to cytosol and in maturation of cytosolic Fe/S enzymes, and mutated in X-linked sideroblastic anemia with ataxia, was significantly down-regulated in RARS. Several dysregulated genes in RARS were restored to the range of normal expression after G-CSF treatment. Of these, MFN2, which was down-regulated in RARS, maintains mitochondrial membrane stability, and restores mitochondrial membrane potential and cell respiration. A normalization of MFN2 is thus consistent with the observed inhibitory effect on cytochrome c release. Several dysregulated genes including BAX, FLIP and BAG1 were not altered by G-CSF treatment, indicating that G-CSF does not exert an unspecific anti-apoptotic effect through the Bcl2 family proteins. Only one, BCLAF1, a transcriptional repressor and pro-apoptotic member of BCL2 family was upregulated in RARS erythroblasts and down-regulated by G-CSF. G-CSF treatment down-regulated also the expression of interferon induced genes including IFIT1, IFIH1, IFI44, IFIT2, IFIT3, IRF7, IFRG28 and IFI78, several of which were previously shown to be upregulated in RARS CD34+ cells (Pellagatti, 2006). Since G-CSF specifically supports erythroblast survival in RARS through inhibition of mitochondria-mediated apoptosis, our findings may lead to further understanding of the molecular mechanisms in RARS and to the identification of candidate genes in this disease. Figure Figure

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Yi, W., H. Haapasalo, C. Holmlund S. Järvelä, O. Raheem, A. T. Bergenheim, Håkan Hedman, and R. Henriksson. "Expression of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins in human ependymoma relates to tumor location, WHO Grade, and patient age." Clinical Neuropathology 28, no. 01 (January 1, 2009): 21–27. http://dx.doi.org/10.5414/npp28021.

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Malcikova, Jitka, Jana Smardova, Daniela Zackova, Tomas Jurcek, Ludmila Rocnova, Martin Trbusek, Alexandra Oltova, et al. "P53 Inactivation and Genomic Aberrations in Relation to Imatinib Resistance in Chronic Myeloid Leukemia." Blood 114, no. 22 (November 20, 2009): 4256. http://dx.doi.org/10.1182/blood.v114.22.4256.4256.

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Abstract Abstract 4256 Background Imatinib resistance in chronic myeloid leukemia (CML) patients is correlated with mutations in BCR-ABL tyrosine kinase domain in about half of the cases. Additional mechanisms related to imatinib resistance are under investigation. As TP53 gene is an important tumor suppressor that triggers apoptosis in response to DNA damage, its inactivation is responsible for chemotherapy resistance in cancer. Its role in cellular response to targeted biological treatment is currently unresolved. Inactivation of p53 by deletion and/or mutation in the TP53 gene is observed in CML patients during progression to accelerated phase (AP) and blast crisis (BC). It was suggested that BCR-ABL inhibition by imatinib induce the p53 response and therefore p53 inactivation may play role in resistance to targeted treatment (Wendel et al., 2006; Yamamoto et al., 2008). On the other hand, imatinib-induced p53 independent pro-apoptotic mechanism was described recently (Liu et al., 2009). Aim We investigated the relationship between imatinib resistance and abnormalities in the TP53 gene and additional genomic changes. Methods RNA and genomic DNA were isolated from peripheral blood mononuclear cells of CML patients that either fail to achieve or lost the major cytogenetic response (MCyR). TP53 mutational status was examined using functional analysis of separated alleles in yeast (FASAY). In defined cases direct sequencing of genomic DNA was used. Genomic changes were detected by conventional metaphase cytogenetics and CGH microarrays 4×44K (Agilent). Copy number analyses were performed using MEV software. Results FASAY analysis to detect functional state of TP53 gene was performed in 16 imatinib-resistant CML patients and in one Ph+ B-ALL patient. Six of these patients were negative for BCR-ABL mutations. Four patients were examined at the time of blast crisis (two patients with myeloid BC and two patients with lymphoid BC). All examined patients carried functional TP53 gene. As FASAY is based on RNA analysis, it is not able to detect some mutations leading to nonsense-mediated RNA decay; therefore, in six patients without BCR-ABL mutation, direct sequencing of TP53 gene from genomic DNA was performed. Also by this approach no TP53 mutation was detected. Alterations of the p53 pathway were found in only 2 patients, both in lymphoid BC: one patient without BCR-ABL mutation had +8 and the deletion of TP53 locus accompanied by i(17p). Second patient with BCR-ABL mutation T315I carried heterozygous deletion of 9p with biallelic loss of 9p21. In this locus two important tumor suppressor genes CDKN2A and CDKN2B are localized. CDKN2A alternative transcript contains an alternate open reading frame (ARF) that functions as a stabilizer of the tumor suppressor protein p53. In other two patients in chronic phase that did not reach MCyR and had no BCR-ABL mutations additional genomic changes potentially connected to imatinib resistance were found: 1) +der(16) coupled with amplification of 16(p11-q12), where ABCC11 and ABCC12 genes are localized. The proteins encoded by these genes are members of the superfamily of ATP-binding cassette (ABC) transporters responsible for multidrug resistance. 2) del(3)(p13p21), involving locus 3p14 where multiple tumor suppressors are localized (e.g. FHIT, ADAMTS9, LRIG1). Chromosomal region 3p14 was shown to be often deleted in different types of human cancers. Conclusions Imatinib resistance in CML patients is probably not associated with TP53 inactivation. Alterations of the p53 pathway occur within transformation to more advanced stages, what is in concordance with previous findings. Genomic aberrations potentially influencing response to imatinib treatment may be found in some patients. Larger patients' cohorts are required to identify relevant recurrent genomic aberrations involved in imatinib resistance. This work was supported with grants NR9858-4/2008 and NR9305-3/2007 provided by IGA MH CR of Czech Republic, and MSM0021622430 provided by MEYS of Czech Republic Disclosures: No relevant conflicts of interest to declare.

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Herdenberg, Carl, Pascal M. Mutie, Ola Billing, Ahmad Abdullah, Rona J. Strawbridge, Ingrid Dahlman, Simon Tuck, et al. "LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes." Communications Biology 4, no. 1 (January 19, 2021). http://dx.doi.org/10.1038/s42003-020-01613-w.

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AbstractLeucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-β) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease.

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Bakherad, Maryam, Mahdieh Salimi, Seyed Abdolhamid Angaji, Frouzandeh Mahjoubi, and Tayebeh Majidizadeh. "LRIG1 expression and colorectal cancer prognosis." BMC Medical Genomics 14, no. 1 (January 18, 2021). http://dx.doi.org/10.1186/s12920-020-00846-2.

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Abstract Background To make the right treatment decisions about colorectal cancer (CRC) patients reliable predictive and prognostic data are needed. However, in many cases this data is not enough. Some studies suggest that LRIG1 gene (leucine-rich repeats and immunoglobulin-like domains1) has prognostic implications in different kinds of cancers. Methods One hundred and two patients with colorectal cancer were retrospectively analyzed for LRIG1 expression at both mRNA and protein levels. SYBR Green Real-Time RT-PCR technique was used for mRNA expression analyses and Glyceraldehyde-3-Phosphate Dehydrogenase gene (GAPDH) was considered as a reference gene for data normalization. LRIG1 protein expression was analyzed using Immunohistochemistry. Additionally, appropriate statistic analyses were used to assess the expression of LRIG1 in test and control groups. The prognostic significance of LRIG1 expression was analyzed using the univariate and multivariate analyses. Results The data revealed that the expression of LRIG1 in both mRNA and protein levels was down regulated in colorectal tumor tissues (P < 0.01) but is not clinically relevant prognostic indicator in CRC. Conclusions Therefore, it is suggested that LRIG1 expression analyses may not be considered as an important issue when making informed and individualized clinical decisions regarding the management of colorectal cancer patients.

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Neirinckx, Virginie, Ann-Christin Hau, Anne Schuster, Sabrina Fritah, Katja Tiemann, Eliane Klein, Petr V. Nazarov, et al. "The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma." Neuro-Oncology Advances 1, no. 1 (May 1, 2019). http://dx.doi.org/10.1093/noajnl/vdz024.

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Abstract Background Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains protein 1) is an RTK inhibitory protein required for stem cell maintenance, and we previously demonstrated the soluble ectodomain of LRIG1 (sLRIG1) to potently inhibit GBM growth in vitro and in vivo. Methods Here, we generated a recombinant protein of the ectodomain of LRIG1 (sLRIG1) and determined its activity in various cellular GBM models including patient-derived stem-like cells and patient organoids. We used proliferation, adhesion, and invasion assays, and performed gene and protein expression studies. Proximity ligation assay and NanoBiT complementation technology were applied to assess protein–protein interactions. Results We show that recombinant sLRIG1 downregulates EGFRvIII but not EGFR, and reduces proliferation in GBM cells, irrespective of their EGFR expression status. We find that sLRIG1 targets and downregulates a wide range of RTKs, including AXL, and alters GBM cell adhesion. Mechanistically, we demonstrate that LRIG1 interferes with AXL but not with EGFR dimerization. Conclusions These results identify AXL as a novel sLRIG1 target and show that LRIG1-mediated RTK downregulation depends on direct protein interaction. The pan-RTK inhibitory activity of sLRIG1 warrants further investigation for new GBM treatment approaches.

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Abdullah, Ahmad, Carl Herdenberg, and Håkan Hedman. "Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling." Scientific Reports 11, no. 1 (April 21, 2021). http://dx.doi.org/10.1038/s41598-021-87949-7.

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AbstractNetrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.

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Sun, Suofeng, Jing Gao, Shen Zhou, Yuan Li, Yu Wang, Li Jin, Jian Li, et al. "A novel circular RNA circ-LRIG3 facilitates the malignant progression of hepatocellular carcinoma by modulating the EZH2/STAT3 signaling." Journal of Experimental & Clinical Cancer Research 39, no. 1 (November 23, 2020). http://dx.doi.org/10.1186/s13046-020-01779-5.

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Abstract Background Circular RNA (circRNA) is emerging as an important player in human diseases, especially cancer. In our previous study, we identified a series of deregulated circRNAs in hepatocellular carcinoma (HCC) by performing circRNA microarray expression profile. Here, we aimed to explore the role of circ-LRIG3 (hsa_circ_0027345) in HCC. Methods qRT-PCR and western blot were used to asses gene and protein expression, respectively. CCK-8, EdU and Transwell assays were used to detect cell proliferation, migration and invasion. GSEA software was applied to analyze the pathway related to circ-LRIG3. Co-IP, RIP and ChIP assays were used to identify the positive feedback axis of circ-LRIG3/EZH2/STAT3. Animal study was carried to test the role of circ-LRIG3 in vivo. Results Circ-LRIG3 was notably upregulated in HCC and promoted HCC cell proliferation, migration, invasion and reduced apoptosis. Circ-LRIG3 formed a ternary complex with EZH2 and STAT3, facilitating EZH2-induced STAT3 methylation and subsequent phosphorylation, resulting in the activation of STAT3 signaling. In turn, activated STAT3 could directly bind to circ-LRIG3 promoter to increase circ-LRIG3 transcription activity, thus forming a positive feedback loop. The animal models showed that exogenous expression of circ-LRIG3 enhanced tumorigenicity and metastasis in vivo, whereas these effects were blocked after treatment with C188–9, a specific STAT3 small-molecule inhibitor. Clinically, high circ-LRIG3 was closely linked with aggressive clinicopathological features and was identified as an independent risk prognostic factor of overall survival. Importantly, plasma circ-LRIG3 was found to be a highly sensitive and specific non-invasive diagnostic indicator for HCC. Conclusions Our study reveals the carcinogenic role of circ-LRIG3 in HCC, which may provide a new therapeutic target for HCC patients.

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Marqués-Torrejón, María Ángeles, Charles A. C. Williams, Benjamin Southgate, Neza Alfazema, Melanie P. Clements, Claudia Garcia-Diaz, Carla Blin, et al. "LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells." Nature Communications 12, no. 1 (May 10, 2021). http://dx.doi.org/10.1038/s41467-021-22813-w.

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AbstractAdult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.

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Sun, Hui, Junwei Zhai, Li Zhang, and Yingnan Chen. "CircRNA LRIG3 knockdown inhibits hepatocellular carcinoma progression by regulating miR-223-3p and MAPK/ERK pathway." Archives of Medical Science, April 15, 2021. http://dx.doi.org/10.5114/aoms/124975.

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IntroductionEmerging evidence suggests that circular RNAs (circRNAs) play critical roles in tumorigenesis. However, the roles and molecular mechanisms of circRNA leucine-rich repeat immunoglobulin domain-containing protein 3 (circ_LRIG3) in hepatocellular carcinoma (HCC) has not been investigated.Material and methodsThe expression levels of circ_LRIG3, miR-223-3p, and mitogen-activated protein kinase kinase 6 (MAP2K6) were determined by qRT-PCR. Flow cytometry was applied to determine the cell cycle distribution and apoptosis. Cell proliferation, migration and invasion were assessed by MTT, colony formation, and transwell assays. Western blot assay was employed to measure the protein levels of the snail, E-cadherin, MAP2K6, mitogen-activated protein kinase (MAPK), phospho-MAPK (p-MAPK), extracellular signal-regulated kinases (ERKs), and phospho-ERKs (p- ERKs). The relationship between miR-223-3p and circ_LRIG3 or MAP2K6 was predicted by bioinformatics tools and verified by dual-luciferase reporter assay. A xenograft tumor model was established to confirm the functions of circ_LRIG3 in vivo.ResultsCirc_LRIG3 and MAP2K6 expression were enhanced while miR-223-3p abundance was reduced in HCC tissues and cells. Knockdown of circ_LRIG3 inhibited cell proliferation, metastasis, and increasing apoptosis. MiR-223-3p was a target of circ_LRIG3, and its downregulation reversed the inhibitory effect of circ_LRIG3 knockdown on the progression of HCC cells. Moreover, MAP2K6 could bind to miR-223-3p, and MAP2K6 upregulation also abolished the suppressive impact of circ_LRIG3 interference on progression of HCC cells. Additionally, the silence of circ_LRIG3 suppressed the activation of the MAPK/ERK pathway and tumor growth by upregulating miR-223-3p and downregulating MAP2K6.ConclusionsCirc_LRIG3 knockdown inhibited HCC progression through regulating miR-223-3p/MAP2K6 axis and inactivating MAPK/ERK pathway.

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Guo, Jing, Xuxian Zhong, Qinglin Tan, Shengnan Yang, Jiaqi Liao, Jinke Zhuge, Ziyang Hong, Qiong Deng, and Qiang Zuo. "miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer." Cell Death & Disease 12, no. 7 (July 2021). http://dx.doi.org/10.1038/s41419-021-03991-3.

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AbstractTrastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.

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Kim, Jongchan. "In silico analysis of differentially expressed genesets in metastatic breast cancer identifies potential prognostic biomarkers." World Journal of Surgical Oncology 19, no. 1 (June 25, 2021). http://dx.doi.org/10.1186/s12957-021-02301-7.

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Abstract Background Identification of specific biological functions, pathways, and appropriate prognostic biomarkers is essential to accurately predict the clinical outcomes of and apply efficient treatment for breast cancer patients. Methods To search for metastatic breast cancer-specific biological functions, pathways, and novel biomarkers in breast cancer, gene expression datasets of metastatic breast cancer were obtained from Oncomine, an online data mining platform. Over- and under-expressed genesets were collected and the differentially expressed genes were screened from four datasets with large sample sizes (N > 200). They were analyzed for gene ontology (GO), KEGG pathway, protein-protein interaction, and hub gene analyses using online bioinformatic tools (Enrichr, STRING, and Cytoscape) to find enriched functions and pathways in metastatic breast cancer. To identify novel prognostic biomarkers in breast cancer, differentially expressed genes were screened from the entire twelve datasets with any sample sizes and tested for expression correlation and survival analyses using online tools such as KM plotter and bc-GenExMiner. Results Compared to non-metastatic breast cancer, 193 and 144 genes were differentially over- and under-expressed in metastatic breast cancer, respectively, and they were significantly enriched in regulating cell death, epidermal growth factor receptor signaling, and membrane and cytoskeletal structures according to the GO analyses. In addition, genes involved in progesterone- and estrogen-related signalings were enriched according to KEGG pathway analyses. Hub genes were identified via protein-protein interaction network analysis. Moreover, four differentially over-expressed (CCNA2, CENPN, DEPDC1, and TTK) and three differentially under-expressed genes (ABAT, LRIG1, and PGR) were further identified as novel biomarker candidate genes from the entire twelve datasets. Over- and under-expressed biomarker candidate genes were positively and negatively correlated with the aggressive and metastatic nature of breast cancer and were associated with poor and good prognosis of breast cancer patients, respectively. Conclusions Transcriptome datasets of metastatic breast cancer obtained from Oncomine allow the identification of metastatic breast cancer-specific biological functions, pathways, and novel biomarkers to predict clinical outcomes of breast cancer patients. Further functional studies are needed to warrant validation of their roles as functional tumor-promoting or tumor-suppressing genes.

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Journal articles on the topic 'LRIG2 protein'

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